Lercamen® efg 10/10

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LERKAMEN® APF 10/10 / LERKAMEN® APF 10/20

Composition:

Active substances: lercanidipine, enalapril;

Lerkamen® APF 10/10: 1 film-coated tablet contains lercanidipine hydrochloride 10 mg, equivalent to lercanidipine 9.44 mg, and enalapril maleate 10 mg, equivalent to enalapril 7.64 mg;

Lerkamen® APF 10/20: 1 film-coated tablet contains lercanidipine hydrochloride 10 mg, equivalent to lercanidipine 9.44 mg, and enalapril maleate 20 mg, equivalent to enalapril 15.29 mg;

Excipients:

lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), povidone K30, sodium hydrogencarbonate, magnesium stearate;

Coating of Lerkamen® APF 10/10 tablet: Opadry 02F29056 (hypromellose 5 cP, titanium dioxide (E 171), talc, macrogol 6000);

Coating of Lerkamen® APF 10/20 tablet: Opadry 02F22330 (hypromellose 5 cP, titanium dioxide (E 171), talc, macrogol 6000, quinoline yellow aluminium lake (E 104), iron oxide yellow (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Lerkamen® APF 10/10: white, round, biconvex film-coated tablets;

Lerkamen® APF 10/20: yellow, round, biconvex film-coated tablets.

Pharmacotherapeutic group. ACE inhibitors and calcium channel blockers: enalapril and lercanidipine. ATC code: C09BB02.

Pharmacological Properties.

Pharmacodynamics.

Lerkamen® ACE is a fixed-dose combination medication containing lercanidipine hydrochloride (a calcium channel blocker) and enalapril maleate (an ACE inhibitor), two antihypertensive agents with complementary mechanisms of action for controlling blood pressure in patients with essential hypertension.

Enalapril.

Enalapril maleate is the maleate salt of enalapril, a derivative of the two amino acids L-alanine and L-proline. Angiotensin-converting enzyme (ACE) is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor angiotensin II. After absorption, enalapril is hydrolyzed to enalaprilat, which inhibits ACE. Inhibition of ACE leads to a reduction in plasma angiotensin II levels, resulting in increased plasma renin activity (due to blockade of the negative feedback mechanism regulating renin release) and decreased aldosterone secretion.

Since ACE is identical to kininase II, enalapril may also inhibit the degradation of bradykinin, a potent vasodilator peptide. However, the role of this mechanism in the therapeutic effect of enalapril has not yet been fully elucidated.

Although enalapril primarily lowers blood pressure by inhibiting the renin-angiotensin-aldosterone system, it remains effective in patients with low plasma renin levels.

In patients with arterial hypertension, enalapril reduces blood pressure in both supine and standing positions without causing a significant increase in heart rate.

Symptomatic orthostatic hypotension is rarely observed. In some patients, normalization of blood pressure occurs over several weeks of treatment. Abrupt discontinuation of enalapril does not lead to a sudden rise in blood pressure.

Effective inhibition of ACE activity typically occurs within 2–4 hours after oral administration of a single dose of enalapril. The onset of antihypertensive effect is usually observed within 1 hour, with maximum reduction in blood pressure occurring 4–6 hours after administration. The duration of action is dose-dependent, but at recommended doses, the antihypertensive and hemodynamic effects last for at least 24 hours.

Hemodynamic studies in patients with essential hypertension have demonstrated that the reduction in blood pressure is associated with a decrease in peripheral vascular resistance and an increase in cardiac output; changes in heart rate were either not observed or were minimal. Renal blood flow increases after enalapril administration, while glomerular filtration rate remains unchanged. There is no evidence of sodium and water retention. However, in patients with low glomerular filtration rate before treatment, these parameters generally improved.

In short-term clinical trials, enalapril administration in patients with and without diabetes mellitus and with kidney disease resulted in reduced albuminuria and decreased urinary excretion of IgG and total urinary protein.

The combination of ACE inhibitors and angiotensin II receptor blockers has been evaluated in two large-scale, randomized, controlled trials (ONTARGET [ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial] and VA NEPHRON-D [The Veterans Affairs Nephropathy in Diabetes]).

ONTARGET was a trial conducted in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. VA NEPHRON-D was a trial conducted in patients with type 2 diabetes and diabetic nephropathy.

These studies did not demonstrate a significant beneficial effect on renal and/or cardiovascular outcomes or mortality, while an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was observed compared to monotherapy. Given the similarity in pharmacodynamic properties, these findings are also applicable to other ACE inhibitors and angiotensin II receptor blockers.

Therefore, the concomitant use of ACE inhibitors and angiotensin II receptor blockers is not recommended in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to evaluate the potential benefit of adding aliskiren to standard therapy with ACE inhibitors or angiotensin II receptor blockers in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The study was terminated early due to an increased risk of adverse outcomes. Cardiovascular mortality and stroke incidence were higher in the aliskiren group compared to the placebo group, and reports of adverse events and serious adverse events (hyperkalemia, hypotension, and renal dysfunction) were more frequent in the aliskiren group than in the placebo group.

Lercanidipine.

Lercanidipine is a dihydropyridine calcium antagonist that inhibits transmembrane calcium influx into cardiac and smooth muscle. Its antihypertensive mechanism of action is based on direct relaxation of vascular smooth muscle, leading to a reduction in total peripheral resistance. Despite its short elimination half-life, lercanidipine has a prolonged antihypertensive effect due to its high membrane partition coefficient and lacks negative inotropic effects due to its high vascular selectivity.

Because vasodilation induced by lercanidipine develops gradually, acute arterial hypotension with reflex tachycardia is rarely observed in patients with arterial hypertension.

As with other asymmetric 1,4-dihydropyridines, the antihypertensive activity of lercanidipine is primarily attributable to the (S)-enantiomer.

Enalapril/Lercanidipine.

The combination of these two agents produces an additive antihypertensive effect, resulting in greater blood pressure reduction than either component alone.

Lerkamen® ACE 10/10.

In a pivotal (double-blind) add-on phase III clinical trial involving 342 patients who did not respond clinically to lercanidipine 10 mg (defined as patients with seated diastolic blood pressure of 95–114 mm Hg and seated systolic blood pressure of 140–189 mm Hg), after 12 weeks of double-blind therapy, the additional reduction in seated systolic blood pressure with the combination of enalapril 10 mg and lercanidipine 10 mg was 5.4 mm Hg greater than with lercanidipine 10 mg alone (-7.7 mm Hg vs. -2.3 mm Hg, p < 0.001). Additionally, the additional reduction in seated diastolic blood pressure was 2.8 mm Hg greater with the combination than with monotherapy (-7.1 mm Hg vs. -4.3 mm Hg, p < 0.001). The proportion of patients achieving a clinical response was significantly higher with combination therapy than with monotherapy: 41% vs. 24% (p < 0.001) for seated systolic blood pressure and 35% vs. 24% (p = 0.032) for seated diastolic blood pressure. Normalization of seated systolic (39% vs. 22%, p < 0.001) and diastolic (29% vs. 19%, p = 0.023) blood pressure occurred significantly more frequently with combination therapy compared to monotherapy. In the subsequent open-label phase of this study, enalapril dose could be increased to 20 mg in combination with 10 mg lercanidipine if blood pressure remained above 140/90 mm Hg: the dose was increased in 133 of 221 patients, and after dose escalation, seated diastolic blood pressure normalized in one-third of patients.

Lerkamen® ACE 10/20.

In a pivotal (double-blind) add-on phase III clinical trial involving 327 patients who did not respond clinically to enalapril 20 mg (defined as patients with seated diastolic blood pressure of 95–114 mm Hg and seated systolic blood pressure of 140–189 mm Hg), the additional reduction in seated systolic blood pressure with the combination of enalapril 20 mg and lercanidipine 10 mg was significantly greater than with monotherapy (-9.8 mm Hg vs. -6.7 mm Hg, p = 0.013). A similar difference was observed for seated diastolic blood pressure reduction (-9.2 mm Hg vs. -7.5 mm Hg, p = 0.015). The proportion of patients with a clinical response was not significantly higher with combination therapy than with monotherapy: 53% vs. 43% (p = 0.076) for seated diastolic blood pressure and 41% vs. 33% (p = 0.116) for seated systolic blood pressure. A slightly higher percentage of patients receiving the combination achieved normalization of seated diastolic (48% vs. 37%, p = 0.055) and systolic (33% vs. 28%, p = 0.325) blood pressure compared to monotherapy.

Pharmacokinetics.

No pharmacokinetic interaction was observed when enalapril and lercanidipine were administered concomitantly.

Enalapril.

Absorption.

After oral administration, enalapril is rapidly absorbed, and peak serum concentrations are reached within 1 hour. Based on urinary recovery, the extent of absorption following oral administration of enalapril maleate is approximately 60%. Food does not affect the absorption of enalapril.

Distribution.

Following absorption, orally administered enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent ACE inhibitor. Peak serum concentrations of enalaprilat occur approximately 4 hours after oral administration of enalapril maleate. The effective half-life of enalaprilat after multiple oral doses of enalapril is 11 hours. In individuals with normal renal function, steady-state serum concentrations of enalaprilat are achieved within 4 days of starting treatment. At concentrations exceeding therapeutic levels, enalaprilat binding to plasma proteins does not exceed 60%.

Biotransformation.

Apart from its conversion to enalaprilat, there is no evidence of significant metabolism of enalapril.

Elimination.

Enalaprilat is primarily eliminated via the kidneys. The main urinary components are enalaprilat (approximately 40% of the administered dose) and unchanged enalapril (approximately 20%).

Renal dysfunction.

Exposure to enalapril and enalaprilat is increased in patients with renal impairment. In patients with mild to moderate renal impairment (creatinine clearance 40–60 mL/min), steady-state AUC of enalaprilat is approximately twice higher than in patients with normal renal function after administration of 5 mg once daily. In severe renal impairment (creatinine clearance ≤ 30 mL/min), AUC increases approximately 8-fold. The effective half-life of enalaprilat after multiple doses of enalapril maleate is prolonged at this level of renal impairment, and the time to reach steady-state concentration is increased (see section "Dosage and administration"). Enalaprilat can be removed from systemic circulation by hemodialysis. Dialysis clearance is 62 mL/min.

Lactation.

Four to six hours after a single 20 mg oral dose, the peak concentration of enalapril in breast milk of five postpartum women averaged 1.7 µg/L (range: 0.54–5.9 µg/L). The average peak concentration of enalaprilat was 1.7 µg/L (range: 1.2–2.3 µg/L); peak concentrations occurred at varying times over 24 hours. Based on peak concentration data in breast milk, it is estimated that a fully breastfed infant would receive no more than 0.16% of the maternal dose adjusted for body weight. In a woman who took 10 mg enalapril orally daily for 11 months, the peak concentration of enalapril (2 µg/L) occurred approximately 4 hours after dose administration, and the peak concentration of enalaprilat (0.75 µg/L) occurred approximately 9 hours after dose administration. The total daily amount of enalapril in breast milk was 1.44 µg/L and enalaprilat was 0.63 µg/L, respectively. Four hours after a single 5 mg enalapril dose in one patient and single 10 mg enalapril doses in two patients, enalaprilat levels in breast milk were below the limit of detection (< 0.2 µg/L); enalapril levels were not determined.

Lercanidipine.

Absorption.

Lercanidipine is completely absorbed after oral administration, and peak plasma concentrations are reached approximately 1.5–3 hours post-dose.

The two enantiomers of lercanidipine exhibit identical plasma profiles: peak time is identical, and peak plasma concentration and AUC are on average 1.2 times higher for the (S)-enantiomer. The elimination half-life of the two enantiomers is essentially the same. In vivo interconversion of the two enantiomers does not occur.

Due to extensive first-pass metabolism, the absolute bioavailability of orally administered lercanidipine under fasting conditions is approximately 10%. However, bioavailability in healthy volunteers under fasting conditions decreases to one-third of this value.

The bioavailability of orally administered lercanidipine increases fourfold when administered 2 hours after a high-fat meal. Therefore, the medication should be taken before meals.

Distribution.

Distribution from plasma to tissues and organs is rapid and extensive.

Plasma protein binding of lercanidipine exceeds 98%. Because protein levels may be reduced in patients with severe renal or hepatic dysfunction, the concentration of free lercanidipine fractions may be higher.

Biotransformation.

Lercanidipine is extensively metabolized by the CYP3A4 enzyme; no parent compound is detected in urine or feces. It is primarily converted into inactive metabolites, and approximately 50% of the dose is excreted in urine.

In vitro experiments with human liver microsomes have demonstrated that lercanidipine weakly inhibits two enzymes—CYP3A4 and CYP2D6—at concentrations 160 and 40 times higher, respectively, than its peak plasma concentrations achieved after a 20 mg dose.

Additionally, interaction studies in humans have shown that lercanidipine does not alter plasma levels of midazolam (a typical CYP3A4 substrate) or metoprolol (a typical CYP2D6 substrate). Therefore, no clinically relevant interaction in the biotransformation of drugs metabolized by CYP3A4 or CYP2D6 is expected when lercanidipine is used at therapeutic doses.

Elimination.

Elimination occurs primarily via biotransformation. The mean terminal elimination half-life is 8–10 hours; due to high affinity for lipid membranes, therapeutic activity persists for up to 24 hours. No accumulation was observed after repeated administration.

Linearity/Non-linearity.

Plasma levels of lercanidipine after oral administration are not directly proportional to dose (non-linear kinetics). After administration of 10, 20, or 40 mg, observed peak plasma concentrations were in the ratio 1:3:8, and areas under the plasma concentration-time curve were in the ratio 1:4:18, indicating progressive saturation of first-pass metabolism. Consequently, bioavailability increases with increasing dose.

Additional information in special populations.

Pharmacokinetics of lercanidipine in elderly patients and in patients with mild to moderate renal or hepatic impairment are similar to those observed in the general patient population. In patients with severe renal impairment or those undergoing dialysis, drug concentrations were higher (approximately 70%). In patients with moderate to severe hepatic impairment, systemic bioavailability of lercanidipine is likely increased, as the drug is normally extensively metabolized in the liver.

Preclinical Safety Data.

Combination of enalapril and lercanidipine.

The potential toxicity of the combined enalapril and lercanidipine formulation was studied in rats: the drug was administered orally for 3 months, and two genotoxicity tests were performed. The toxicological profile of the combination did not differ from that of the individual components when administered separately.

Separate data are available for each of the two components—enalapril and lercanidipine.

Enalapril.

Preclinical data from traditional safety pharmacology, repeated-dose toxicity, genotoxicity, and carcinogenicity studies revealed no special hazard for humans.

Reproductive toxicity studies suggest that enalapril does not affect fertility or reproductive function in rats and is not teratogenic. However, when administered to female rats before mating and throughout pregnancy and lactation, increased offspring mortality was observed. The drug crosses the placenta and is excreted in milk. It has been shown that ACE inhibitors may adversely affect late fetal development, potentially leading to fetal death and craniofacial malformations. Additionally, fetotoxicity, delayed intrauterine development, and patent ductus arteriosus have been reported. These developmental abnormalities may be partially explained by the direct effect of ACE inhibitors on the fetal renin-angiotensin system, and partially by maternal hypotension-induced ischemia, reduced fetoplacental blood flow, and decreased oxygen and nutrient supply to the fetus.

Lercanidipine.

Data from standard preclinical safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential, and reproductive toxicity studies indicate no special hazard for humans.

Significant effects observed in long-term studies in rats and dogs were directly or indirectly related to the known effects of high doses of calcium antagonists, i.e., resulting from excessive pharmacodynamic activity.

Lercanidipine treatment did not affect fertility or general reproductive function in rats; however, administration of high doses led to pre- and post-implantation loss and delayed intrauterine development. Teratogenic effects of lercanidipine were not observed in studies in rats and rabbits, although teratogenicity has been reported for other dihydropyridine derivatives in animal studies. Administration of high doses of lercanidipine (12 mg/kg/day) during delivery may lead to dystocia.

The distribution of lercanidipine and/or its metabolites in pregnant animals and their excretion into milk has not been studied.

Clinical characteristics.

Indications.

Lerkamen® ACE 10/10:

treatment of essential hypertension in patients whose blood pressure is not adequately controlled with monotherapy using lercanidipine hydrochloride 10 mg. Initiation of arterial hypertension treatment with the combination drug Lerkamen® ACE 10/10 is not recommended.

Lerkamen® ACE 10/20:

treatment of essential hypertension in patients whose blood pressure is not adequately controlled with monotherapy using enalapril maleate 20 mg. Initiation of arterial hypertension treatment with the combination drug Lerkamen® ACE 10/20 is not recommended.

Contraindications.

• Hypersensitivity to any angiotensin-converting enzyme (ACE) inhibitor or dihydropyridine calcium channel blockers, or to any of the excipients (see section "Composition").
• History of angioedema associated with previous ACE inhibitor therapy.
• Hereditary or idiopathic angioedema.
• Pregnancy or planned pregnancy (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").
• Obstruction of blood outflow from the left ventricle.
• Congestive heart failure not previously treated.
• Unstable angina or within one month following myocardial infarction.
• Severe renal impairment (GFR < 30 mL/min), including patients on hemodialysis.
• Severe hepatic impairment.
• Concomitant use with:
• potent CYP3A4 inhibitors (see section "Interaction with other medicinal products and other forms of interaction");
• cyclosporine (see section "Interaction with other medicinal products and other forms of interaction");
• grapefruit or grapefruit juice (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use in combination with sacubitril/valsartan therapy. Enalapril should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").
• Concomitant use of Lerkamen® ACE with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal dysfunction (GFR < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").

Interaction with other medicinal products and other forms of interaction.

The antihypertensive effect of Lerkamen® ACE may be enhanced by other medicinal products that lower blood pressure, such as diuretics, β-blockers, α-blockers, and other substances.

Additionally, the following interactions have been observed with each of the active substances of this medicinal product.

Enalapril maleate.

Medicinal products that increase the risk of angioedema.

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Special precautions for use").

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin may increase the risk of developing angioedema (see section "Special precautions for use").

Double blockade of the renin-angiotensin-aldosterone system (RAAS).

Clinical trial data indicate that dual blockade of the renin-angiotensin-aldosterone system (RAAS) associated with concomitant use of ACE inhibitors and angiotensin II receptor blockers or aliskiren leads to an increased incidence of adverse events such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to use of a single agent acting on the RAAS (see sections "Contraindications", "Special precautions for use", and "Pharmacodynamics").

Potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes.

Serum potassium levels usually remain within normal limits; however, hyperkalemia may occur in some patients receiving enalapril. Potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium-containing supplements, or potassium salts may lead to a significant increase in serum potassium concentration. Caution is advised when enalapril is used concomitantly with other medicinal products that increase serum potassium levels, such as trimethoprim or co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim acts as a potassium-sparing diuretic, similar to amiloride. Therefore, combination of enalapril with the above-mentioned agents is not recommended. If these agents are co-administered due to documented hypokalemia, they should be used with caution and under frequent monitoring of serum potassium levels (see section "Special precautions for use").

Cyclosporine.

Concomitant use of ACE inhibitors and cyclosporine may lead to hyperkalemia. Monitoring of serum potassium levels is recommended.

Heparin.

Concomitant use of ACE inhibitors and heparin may lead to hyperkalemia. Monitoring of serum potassium levels is recommended.

Diuretics (thiazide and loop diuretics).

Prior treatment with high doses of diuretics may lead to reduced blood volume and risk of arterial hypotension at the start of enalapril therapy (see section "Special precautions for use"). Hypotensive effects may be minimized by discontinuation of diuretics, increased salt or fluid intake, or initiation with a low dose of enalapril.

Other antihypertensive agents.

Concomitant use of these agents may enhance the hypotensive effect of enalapril. Concomitant use with nitroglycerin and other nitrates or vasodilators may result in additional reduction of blood pressure.

Lithium.

Reversible increases in serum lithium concentration and enhanced lithium toxicity have been observed during concomitant use of lithium with ACE inhibitors. Concomitant use of thiazide diuretics may increase lithium levels and thereby enhance lithium toxicity when used together with ACE inhibitors. Therefore, concomitant use of enalapril with lithium-containing medicinal products is not recommended; however, if co-administration is necessary, careful monitoring of serum lithium levels is required (see section "Special precautions for use").

Tricyclic antidepressants/antipsychotics/anesthetics/opioids.

Additional reduction in blood pressure may occur when certain anesthetics, tricyclic antidepressants, and antipsychotics are used concomitantly with ACE inhibitors (see section "Special precautions for use").

Nonsteroidal anti-inflammatory drugs, including selective cyclooxygenase-2 (COX-2) inhibitors.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, may reduce the efficacy of diuretics and other antihypertensive agents. Therefore, the antihypertensive effect of angiotensin II receptor antagonists or ACE inhibitors may be reduced when used concomitantly with NSAIDs, including selective COX-2 inhibitors.

Concomitant use of NSAIDs (including selective COX-2 inhibitors) and angiotensin II receptor antagonists or ACE inhibitors may have an additive effect on increasing serum potassium levels and may lead to deterioration of renal function. These effects are generally reversible. In rare cases, acute renal failure may develop, particularly in patients with impaired renal function (e.g., elderly patients or dehydrated patients, including those receiving diuretic therapy). Therefore, concomitant use of these agents should be prescribed with caution, especially in patients with impaired renal function. Patients should receive adequate hydration. Renal function should be monitored periodically after initiation and during concomitant therapy.

Gold-containing medicinal products.

When ACE inhibitors, including enalapril, are used concomitantly with injectable gold compounds (sodium aurothiomalate), rare nitritoid reactions have been reported, characterized by symptoms such as facial flushing, nausea, vomiting, and arterial hypotension.

Sympathomimetics.

Sympathomimetics may attenuate the antihypertensive effect of ACE inhibitors.

Antidiabetic agents.

Epidemiological studies suggest that concomitant use of ACE inhibitors with antidiabetic agents (insulin, oral hypoglycemic agents) may lead to decreased blood glucose levels and risk of hypoglycemia. This phenomenon is most likely to occur during the first weeks of combined therapy and in patients with impaired renal function (see sections "Special precautions for use" and "Adverse reactions").

Alcohol.

Alcohol enhances the hypotensive effect of ACE inhibitors.

Acetylsalicylic acid, thrombolytics, and β-blockers.

Concomitant use of enalapril with acetylsalicylic acid (at cardiologic doses), thrombolytics, and β-blockers is not associated with risk.

Lercanidipine.

Concomitant use is contraindicated.

CYP3A4 inhibitors.

Lercanidipine is known to be metabolized by the CYP3A4 enzyme; therefore, concomitant administration of CYP3A4 inhibitors may affect the metabolism and excretion of lercanidipine.

In a drug interaction study with ketoconazole, a potent CYP3A4 inhibitor, a significant increase in plasma concentrations of lercanidipine was observed (15-fold increase in the area under the concentration-time curve (AUC) and 8-fold increase in Cmax of the S-enantiomer of lercanidipine).

Combined use of lercanidipine with potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin, clarithromycin) is contraindicated (see section "Contraindications").

Cyclosporine.

After concomitant use, increased plasma concentrations of both lercanidipine and cyclosporine were observed. A study in young healthy volunteers showed that when cyclosporine was administered 3 hours after lercanidipine, plasma levels of lercanidipine were unchanged, but cyclosporine AUC increased by 27%. When lercanidipine and cyclosporine were administered simultaneously, a 3-fold increase in plasma lercanidipine levels and a 21% increase in cyclosporine AUC were observed.

Cyclosporine and lercanidipine should not be used together (see section "Special precautions for use").

Grapefruit or grapefruit juice.

As with other dihydropyridines, the metabolism of lercanidipine is slowed by grapefruit or grapefruit juice, resulting in increased systemic availability of lercanidipine and enhanced hypotensive effect.

Lercanidipine should not be taken with grapefruit or grapefruit juice (see section "Contraindications").

Concomitant use is not recommended.

CYP3A4 inducers.

Caution is advised when lercanidipine is used concomitantly with CYP3A4 inducers such as anticonvulsants (e.g., phenytoin, phenobarbital, carbamazepine) and rifampicin, as the antihypertensive effect of lercanidipine may be reduced, and blood pressure should be monitored more frequently than usual (see section "Special precautions for use").

Alcohol.

Alcohol consumption should be avoided as it may enhance the vasodilatory effect of antihypertensive agents (see section "Special precautions for use").

Safety measures, including dose adjustment.

CYP3A4 substrates.

Caution is advised when lercanidipine is co-administered with other CYP3A4 substrates such as terfenadine, astemizole, and class III antiarrhythmics (e.g., amiodarone, quinidine, sotalol).

Midazolam.

In elderly volunteers, concomitant oral administration of midazolam 20 mg enhanced the absorption of lercanidipine (by approximately 40%) but reduced its absorption rate (tmax increased from 1.75 to 3 hours). Midazolam concentration was unchanged.

Metoprolol.

Concomitant use of lercanidipine and metoprolol (a β-blocker primarily eliminated via the liver) did not alter the bioavailability of metoprolol, whereas the bioavailability of lercanidipine decreased by 50%. This effect may result from reduced hepatic blood flow caused by β-blockers and may also occur with other agents in this class. Therefore, lercanidipine can be safely used concomitantly with β-adrenergic receptor blockers, but dose adjustment may be required.

Digoxin.

Concomitant administration of 20 mg lercanidipine in patients chronically receiving β-methyldigoxin did not reveal any pharmacokinetic interaction. However, a 33% increase in digoxin Cmax (mean maximum value) was observed, while no significant changes occurred in AUC or renal clearance. Patients receiving lercanidipine and digoxin concomitantly should be closely monitored for possible clinical signs of digoxin toxicity.

Concomitant use with other medicinal products.

Fluoxetine.

An interaction study between lercanidipine and fluoxetine, a CYP2D6 and CYP3A4 inhibitor, conducted in healthy volunteers aged 65±7 years (mean ± standard deviation), did not reveal any clinically significant modification of lercanidipine pharmacokinetics.

Cimetidine.

Concomitant use of cimetidine 800 mg daily does not cause significant changes in plasma lercanidipine levels; however, caution is required when higher cimetidine doses are used, as bioavailability and hence the hypotensive effect of lercanidipine may increase.

Simvastatin.

When lercanidipine 20 mg was repeatedly co-administered with simvastatin 40 mg, the AUC of lercanidipine changed insignificantly, whereas the AUC of simvastatin increased by up to 56% and the AUC of its main metabolite, β-hydroxy acid, by up to 28%. Such changes are unlikely to be clinically significant. No interaction is expected if lercanidipine is taken in the morning and simvastatin in the evening, as demonstrated for drugs in this class.

Warfarin.

Concomitant administration of lercanidipine 20 mg on an empty stomach to healthy volunteers did not alter the pharmacokinetics of warfarin.

Diuretics and ACE inhibitors.

Lercanidipine can be safely used concomitantly with diuretics and ACE inhibitors.

Other medicinal products affecting blood pressure.

As with other antihypertensive agents, enhanced hypotensive effects may occur when lercanidipine is used concomitantly with other agents affecting blood pressure, such as α-blockers used for urinary symptoms, tricyclic antidepressants, or neuroleptics. Conversely, reduced hypotensive effect may occur when used concomitantly with corticosteroids.

Children.

Interaction studies have been conducted only in adults.

Special precautions for use.

Symptomatic arterial hypotension.

Symptomatic arterial hypotension rarely occurs in patients with uncomplicated arterial hypertension. When treating hypertensive patients with enalapril, the risk of symptomatic hypotension increases if fluid and electrolyte balance is disturbed and fluid loss occurs, for example, after diuretic therapy, a low-salt diet, dialysis, diarrhea, or vomiting (see section "Interaction with other medicinal products and other forms of interaction"). Symptomatic hypotension has been observed in patients with heart failure (with or without concomitant renal impairment). It occurs more frequently in patients with more severe heart failure, often associated with the use of high doses of loop diuretics, hyponatremia, or impaired renal function. Treatment of such patients should be initiated under medical supervision, and continued monitoring is required when adjusting the dose of enalapril and/or diuretic. These same recommendations apply to patients with ischemic heart disease or cerebrovascular disease, in whom excessive reduction in blood pressure may lead to myocardial infarction or acute cerebrovascular accident.

In case of arterial hypotension, the patient should be placed in a supine position and, if necessary, receive intravenous infusion of physiological saline. Reversible hypotensive effect is not a contraindication to further use of the drug, which may be continued after blood pressure has increased following volume repletion.

In some patients with heart failure and normal or low blood pressure, enalapril may cause additional reduction in blood pressure. This effect is expected and usually not a reason to discontinue therapy. If arterial hypotension becomes symptomatic, dose reduction and/or discontinuation of the diuretic and/or enalapril may be necessary.

Sinus node dysfunction.

Lercanidipine should be administered with caution to patients with sinus node dysfunction if a pacemaker has not been implanted.

Left ventricular dysfunction.

Although hemodynamically controlled studies have not revealed any disturbances in ventricular function, lercanidipine should be used with caution in patients with left ventricular dysfunction.

Ischemic heart disease.

It is presumed that the use of certain short-acting dihydropyridine derivatives may be associated with increased cardiovascular risk in patients with ischemic heart disease. Although lercanidipine is a long-acting agent, caution is required when administering it to such patients.

In rare cases, the use of some dihydropyridine derivatives may cause precordial pain or angina. Very rarely, in patients with existing angina attacks, their frequency, duration, and severity may increase. Isolated cases of myocardial infarction are possible (see section "Adverse reactions").

Use in renal impairment.

Particular caution is required when using enalapril in patients with mild or moderate renal impairment. Routine monitoring of these patients should include regular assessment of serum potassium and creatinine levels. Reports of renal failure associated with enalapril use have mainly involved patients with severe heart failure or underlying kidney disease, including renal artery stenosis. With timely diagnosis and appropriate treatment, enalapril-induced renal failure is reversible. In some patients with arterial hypertension without prior kidney disease, combined use of enalapril and a diuretic may lead to increased blood urea and creatinine levels. Dose reduction of enalapril and/or discontinuation of the diuretic may be necessary. In such cases, the presence of renal artery stenosis should be considered (see section "Special precautions for use. Renovascular hypertension").

Renovascular hypertension.

The use of ACE inhibitors in patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney increases the risk of arterial hypotension and renal failure. In such cases, renal dysfunction may be accompanied by only minor changes in serum creatinine concentration. Treatment of these patients should be initiated under direct medical supervision using low doses and cautious dose titration, with close monitoring of renal function.

Kidney transplantation.

There is no experience with the use of lercanidipine and enalapril in patients who have recently undergone kidney transplantation. Therefore, the use of Lerкамen® АРF is not recommended in such patients.

Hepatic impairment.

The antihypertensive effect of lercanidipine may be enhanced in patients with impaired liver function. Rarely, when using ACE inhibitors, a syndrome has been observed that begins with cholestatic jaundice or hepatitis, rapidly progressing to fulminant hepatic necrosis, sometimes with fatal outcome. The mechanism of this syndrome is unclear. Patients who develop jaundice or a marked increase in liver enzymes while receiving ACE inhibitors should discontinue the drug and receive appropriate treatment.

Peritoneal dialysis.

Lercanidipine intake has been associated with turbidity of dialysate in patients undergoing peritoneal dialysis. The turbidity is due to increased triglyceride concentration in the drained dialysate. Although the mechanism of this phenomenon is not fully understood, the turbidity resolves shortly after discontinuation of lercanidipine. This characteristic should be taken into account, as dialysate turbidity may be mistakenly interpreted as infectious peritonitis, potentially leading to unnecessary hospitalization and empirical antibiotic therapy.

Neutropenia/agranulocytosis.

Neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia occurs rarely in patients with normal renal function and without special risk factors. Enalapril should be used with particular caution in patients with vascular collagenosis, those receiving immunosuppressive agents, allopurinol, procainamide, or those with several of these risk factors, especially with pre-existing renal impairment. Severe infections resistant to antibiotic therapy have developed in some patients. In such patients receiving enalapril, regular monitoring of the leukocyte count is recommended, and patients should be instructed to report any signs of infection to their physician.

Hypersensitivity/angioedema.

Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has been reported during treatment with ACE inhibitors, particularly enalapril. This swelling may develop at any time during treatment. In such cases, enalapril should be discontinued immediately; the patient must remain under medical supervision until all symptoms have completely resolved. Even if swelling affects only the tongue without concomitant respiratory distress, prolonged observation is required, as treatment with antihistamines and corticosteroids may be insufficient.

In rare cases, death has been reported due to laryngeal or lingual angioedema. When swelling involves the tongue, glottis, or larynx, there is an increased risk of airway obstruction, especially in patients who have undergone airway surgery.

If swelling extends to the tongue, glottis, or larynx and may cause airway obstruction, immediate appropriate treatment should be initiated, which may include subcutaneous administration of 1:1000 adrenaline solution (0.3 mL–0.5 mL) and/or measures to secure airway patency.

Angioedema occurs more frequently in patients of African descent compared to other patients receiving ACE inhibitors.

Patients with a history of angioedema of other etiology belong to a high-risk group for this complication when prescribed ACE inhibitors (see section "Contraindications").

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Initiation of sacubitril/valsartan therapy should not occur earlier than 36 hours after the last dose of enalapril. Enalapril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin may increase the risk of angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) (see section "Interaction with other medicinal products and other forms of interaction").

Caution is required when initiating racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin in patients already receiving ACE inhibitors.

Anaphylactoid reactions during desensitization therapy for hymenoptera venom.

Life-threatening anaphylactoid reactions rarely occur when ACE inhibitors are used concomitantly with desensitization therapy for hymenoptera venom. These reactions can be avoided by temporarily discontinuing the ACE inhibitor before starting desensitization therapy.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis.

Life-threatening anaphylactoid reactions rarely occur when ACE inhibitors are used concomitantly with LDL apheresis using dextran sulfate. These reactions can be avoided by temporarily discontinuing the ACE inhibitor before each apheresis procedure.

Hypoglycemia.

In patients with diabetes receiving oral antidiabetic agents or insulin, careful monitoring for hypoglycemia is required at the beginning of ACE inhibitor therapy, especially during the first month of combination therapy (see section "Interaction with other medicinal products and other forms of interaction").

Cough.

Cough has been reported during treatment with ACE inhibitors. The cough is usually non-productive and resolves after discontinuation of the drug. Cough due to ACE inhibitor therapy should be considered in the differential diagnosis of cough.

Surgery/anesthesia.

During major surgical procedures or anesthesia using agents that cause arterial hypotension, enalapril inhibits the formation of angiotensin II secondary to compensatory renin release. If arterial hypotension occurs that can be explained by these mechanisms, it may be corrected by increasing fluid volume.

Serum potassium.

ACE inhibitors may cause hyperkalemia as they suppress aldosterone release. This effect is usually minor in patients with normal renal function. However, hyperkalemia may occur in patients with impaired renal function and/or in patients taking potassium supplements (including salt substitutes), potassium-sparing diuretics, trimethoprim, or co-trimoxazole (trimethoprim/sulfamethoxazole), and especially aldosterone antagonists or angiotensin receptor blockers. Potassium-sparing diuretics and angiotensin receptor blockers should be used with caution in patients receiving ACE inhibitors, and serum potassium levels and renal function should be monitored (see section "Interaction with other medicinal products and other forms of interaction").

Lithium.

The combination of lithium and enalapril is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Dual blockade of the renin-angiotensin-aldosterone system (RAAS).

Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").

If dual blockade therapy is absolutely necessary, it should be conducted only under specialist supervision, with careful monitoring of renal function, electrolyte levels, and blood pressure.

Concomitant use of ACE inhibitors and angiotensin II receptor blockers is not indicated in patients with diabetic nephropathy.

CYP3A4 inducers.

CYP3A4 inducers such as anticonvulsants (e.g., phenytoin, carbamazepine) and rifampicin may reduce serum lercanidipine levels, potentially resulting in lower than expected efficacy of lercanidipine (see section "Interaction with other medicinal products and other forms of interaction").

Ethnic differences.

As with other ACE inhibitors, the antihypertensive effect of enalapril may be less pronounced in patients of African descent compared to patients of other races, possibly due to a higher prevalence of low renin levels in this population.

Pregnancy.

This medicinal product is contraindicated in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this medicinal product, its use must be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.

Lactation.

Lerкамen® АРF is not recommended during lactation (see section "Use during pregnancy or breastfeeding").

Children.

The safety and efficacy of this combined medicinal product in children have not been established in controlled studies.

Alcohol.

Alcohol consumption should be avoided as it may enhance the vasodilatory antihypertensive effect of medicinal products (see section "Interaction with other medicinal products and other forms of interaction").

Lactose.

This medicinal product contains lactose. Patients with hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take Lerкамen® АРF.

Sodium.

This medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy.

Enalapril.

The use of ACE inhibitors (enalapril) is not recommended during the first trimester of pregnancy (see section "Special precautions for use"). The use of ACE inhibitors (enalapril) is contraindicated during the second and third trimesters of pregnancy (see sections "Contraindications" and "Special precautions for use").

Epidemiological data on the risk of teratogenic effects associated with ACE inhibitor use during the first trimester of pregnancy do not allow definitive conclusions; however, a slight increase in risk cannot be excluded. Women planning pregnancy should have their ACE inhibitor therapy replaced with an alternative antihypertensive agent with an established safety profile during pregnancy, except when ACE inhibitor therapy is considered necessary. When pregnancy is diagnosed, treatment with ACE inhibitors should be discontinued immediately, and alternative therapy initiated if necessary.

The use of ACE inhibitors during the second and third trimesters of pregnancy causes fetotoxic effects in humans (impaired renal function, oligohydramnios, delayed ossification of skull bones) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia) (see section "*Preclinical safety data"). Oligohydramnios in the mother may occur, possibly as a manifestation of impaired fetal renal function, potentially leading to limb contractures, craniofacial deformities, and pulmonary hypoplasia. If an ACE inhibitor is used from the second trimester of pregnancy, ultrasound examination of patients should be performed to assess fetal renal function and skull ossification. Newborns whose mothers received ACE inhibitors should be monitored for arterial hypotension (see sections "Contraindications" and "Special precautions for use").

Lercanidipine.

There are no data on the use of lercanidipine in pregnant women. Animal studies did not reveal teratogenic effects (see section "Preclinical safety data"), although such effects have been observed with other dihydropyridine compounds.

Lercanidipine is not recommended for use in pregnant women or women of childbearing potential who are not using effective contraception (see section "Special precautions for use").

Combination of enalapril and lercanidipine.

Data on the use of enalapril maleate/lercanidipine hydrochloride in pregnant women are insufficient or lacking. Animal studies are inadequate to draw conclusions on reproductive toxicity (see section "Preclinical safety data").

Accordingly, the use of Lerкамen® АРF is contraindicated in pregnant women and women planning pregnancy. When pregnancy is diagnosed, treatment with this medicinal product should be discontinued immediately, and alternative therapy initiated if necessary.

Breastfeeding.

Enalapril.

Some pharmacokinetic data show very low concentrations of enalapril in breast milk (see section "Pharmacokinetics"). Although low concentrations of ACE inhibitors are not clinically significant, due to the hypothetical risk of adverse reactions in infants (effects on the cardiovascular system and renal function) and the lack of clinical experience, enalapril therapy is not recommended in breastfeeding mothers of premature infants or infants in the first weeks of life. Breastfeeding of older infants may allow the mother to take Lerкамen® АРF only in cases of extreme necessity and under medical supervision for monitoring adverse reactions in the infant.

Lercanidipine.

Data on the excretion of lercanidipine/metabolites in breast milk are lacking. Risk to newborns/infants cannot be excluded. Lercanidipine should not be used during breastfeeding.

Combination of enalapril and lercanidipine.

Accordingly, Lerкамen® АРF is not recommended during breastfeeding.

Fertility.

Clinical data on lercanidipine are lacking. Cases have been reported in which some patients receiving calcium channel blockers developed reversible biochemical changes in the sperm head, potentially negatively affecting fertilization. In cases of repeated unsuccessful attempts at in vitro fertilization and in the absence of other explanations, the possibility that calcium channel blockers may be the cause of these failures should be considered.

Ability to affect reaction speed when driving or operating machinery.

Lerкамen® АРF has a negligible effect on the ability to drive or operate machinery. However, caution is advised, as dizziness, asthenia, fatigue, and, rarely, somnolence may occur (see section "Adverse reactions").

Method of Administration and Dosage.

Lerkamen® ACE 10/10.

If the patient's blood pressure is insufficiently controlled on monotherapy with lercanidipine hydrochloride 10 mg, treatment may be continued either by increasing the dose of lercanidipine hydrochloride to 20 mg or by using the fixed-dose combination medicinal product Lerkamen® ACE 10/10.

Individual dose titration should be considered based on the components of the drug. In clinically appropriate cases, direct substitution of monotherapy with a fixed-dose combination product is possible.

Lerkamen® ACE 10/20.

If the patient's blood pressure is insufficiently controlled on monotherapy with enalapril maleate 20 mg, treatment may be continued with higher doses of enalapril maleate or by using the fixed-dose combination medicinal product Lerkamen® ACE 10/20.

Individual dose titration should be considered based on the components of the drug. In clinically appropriate cases, direct substitution of monotherapy with a fixed-dose combination product is possible.

Dosage.

The recommended dose is one tablet once daily, taken at least 15 minutes before a meal.

Elderly patients.

Dosage depends on the patient's renal status (see section "Patients with Renal Impairment").

Patients with Renal Impairment.

Lerkamen® ACE is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) or those undergoing hemodialysis (see sections "Contraindications" and "Special Warnings and Precautions for Use"). Caution should be exercised when administering the drug to patients with mild or moderate renal impairment.

Patients with Hepatic Impairment.

Lerkamen® ACE is contraindicated in patients with severe hepatic impairment. Caution should be exercised when administering the drug to patients with mild or moderate hepatic impairment.

Method of Administration.

Precautions during administration or handling of this medicinal product:

• the drug should preferably be taken in the morning, at least 15 minutes before breakfast;
• this drug should not be taken with grapefruit juice (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Contraindications").

Children.

Lerkamen® ACE is not indicated for the treatment of arterial hypertension in children.

Overdose.

In post-marketing experience, several cases of intentional overdose requiring hospitalization have been reported following ingestion of enalapril/lercanidipine at doses ranging from 100 to 1000 mg of each substance. Symptoms reported (reduction in systolic pressure, bradycardia, restlessness, somnolence, and flank pain) may have been due to concomitant use of other medicinal products in high doses (e.g., β-blockers).

Symptoms of overdose with enalapril and lercanidipine separately.

The most prominent signs of enalapril overdose reported to date are profound arterial hypotension (occurring approximately six hours after tablet ingestion), associated with blockade of the renin-angiotensin system and stupor. In cases of ACE inhibitor overdose, the following symptoms may develop: acute circulatory failure, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. After ingestion of 300 mg and 440 mg of enalapril, serum enalaprilat levels were approximately 100 and 200 times higher, respectively, than levels typically observed after therapeutic doses.

As with other dihydropyridines, lercanidipine overdose causes marked peripheral vasodilation with significant hypotension and reflex tachycardia. However, at very high doses, peripheral selectivity may be lost, leading to bradycardia and negative inotropic effects. The most common adverse reactions associated with overdose were hypotension, dizziness, headache, and palpitations.

Treatment in case of overdose with enalapril and lercanidipine separately.

In case of enalapril overdose, intravenous infusion of physiological saline solution is recommended. If arterial hypotension develops, the patient should be placed in a supine position. Infusion of angiotensin II and/or intravenous administration of catecholamines should be considered if possible. If treatment is initiated soon after tablet ingestion, measures to remove enalapril maleate from the gastrointestinal tract should be taken (e.g., by inducing emesis, gastric lavage, administration of adsorbents, or sodium sulfate). Enalaprilat can be removed from the circulation by hemodialysis (see section "Special Warnings and Precautions for Use"). In cases of persistent bradycardia, therapy with a cardiac stimulator is indicated. Vital signs, serum electrolyte concentrations, and creatinine levels should be continuously monitored.

In cases of lercanidipine overdose, clinically significant hypotension requires active cardiovascular support, including frequent monitoring of cardiac and respiratory function, placing the patient in a supine position with elevated lower limbs, and monitoring circulating fluid volume and urine output. Due to the prolonged pharmacological effect of lercanidipine, cardiovascular status should be monitored for at least 24 hours. Since the drug has a high protein-binding capacity, dialysis is unlikely to be effective. Patients with expected mild to severe intoxication should be observed under strict medical supervision.

Adverse reactions.

Short description of the safety profile.

The safety of Lerкамen® APF was evaluated in five double-blind controlled clinical studies and in two long-term open-label extension phases. Overall, 1141 patients received Lerкамen® APF. Adverse reactions associated with this combination therapy correspond to those observed with the individual components of the medicinal product when administered separately. The most commonly reported adverse reactions during treatment with Lerкамen® APF are cough (4.03%), dizziness (1.67%), and headache (1.67%).

Short description of adverse reactions in table form.

The table below lists adverse reactions reported during clinical trials of Lerкамen® APF, which have a clear causal relationship, classified by MedDRA organ systems and frequency of occurrence. Frequency categories: very common (> 1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); not known (cannot be estimated from available data).

Adverse reactions that occurred in only one patient are listed with the frequency "rarely".

Additional information on individual components.

Adverse reactions reported for either of the components (enalapril or lercanidipine) may also be potential adverse reactions of the medicine LERKAMEN® ACE, even if they were not observed during clinical trials or in the post-marketing period.

Enalapril individually.

Enalapril may cause the following adverse reactions.

Disorders of the blood and lymphatic system.

Uncommon: anaemia (including aplastic and haemolytic).

Rare: neutropenia, decreased haemoglobin concentration, decreased haematocrit, thrombocytopenia, agranulocytosis, bone marrow suppression, pancytopenia, lymphadenopathy, autoimmune disorders.

Endocrine system disorders.

Unknown frequency: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders.

Uncommon: hypoglycaemia (see section "Special precautions for use").

Psychiatric disorders.

Common: depression.

Uncommon: confusion, increased excitability, insomnia.

Rare: pathological dreams, sleep disorders.

Nervous system disorders.

Very common: dizziness.

Common: headache, syncope, taste disturbances.

Uncommon: somnolence, paraesthesia, vertigo.

Eye disorders.

Very common: blurred vision.

Ear and labyrinth disorders.

Uncommon: tinnitus.

Cardiac disorders.

Common: chest pain, arrhythmia, angina pectoris, tachycardia.

Uncommon: palpitations, myocardial infarction or cerebrovascular accident*, probably secondary to severe hypotension in patients at risk (see section "Special precautions for use").

* Incidence compared to placebo and active control groups in clinical trials.

Vascular disorders.

Common: hypotension (including orthostatic hypotension).

Uncommon: flushing, orthostatic hypotension.

Rare: Raynaud's phenomenon.

Respiratory, thoracic and mediastinal disorders.

Very common: cough.

Common: dyspnoea.

Uncommon: rhinorrhoea, sore throat or hoarseness, bronchospasm/asthma.

Rare: pulmonary infiltrates, rhinitis, allergic alveolitis/eosinophilic pneumonia.

Gastrointestinal disorders.

Very common: nausea.

Common: diarrhoea, abdominal pain.

Uncommon: intestinal obstruction, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritation, dry mouth, peptic ulcers.

Rare: stomatitis/aphthous ulcers, glossitis.

Very rare: intestinal angioedema.

Hepatobiliary disorders.

Rare: hepatic failure, hepatitis (hepatocellular or cholestatic), hepatitis with necrosis, cholestasis (including with jaundice).

Skin and subcutaneous tissue disorders.

Common: rash, hypersensitivity/angioedema (cases of angioedema of the face, extremities, lips, tongue, glottis and/or larynx have been reported (see section "Special precautions for use").

Uncommon: hyperhidrosis, pruritus, urticaria, alopecia.

Rare: erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, pemphigus, erythroderma.

A symptom complex has been described which may include: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, positive ANA titre, elevated ESR, eosinophilia and leukocytosis. Skin rash, photosensitivity or other skin disorders may occur.

Musculoskeletal, connective tissue and bone disorders.

Uncommon: muscle cramps.

Renal and urinary disorders.

Uncommon: renal dysfunction, renal failure, proteinuria.

Rare: oliguria.

Reproductive system and breast disorders.

Uncommon: impotence.

Rare: gynaecomastia.

General disorders.

Very common: asthenia.

Common: fatigue.

Uncommon: weakness, fever.

Investigations.

Common: hyperkalaemia, increased serum creatinine concentration.

Uncommon: increased blood urea concentration, hyponatraemia.

Rare: increased liver enzyme activity, increased serum bilirubin level.

Lercanidipine individually.

In controlled clinical studies and during the post-marketing period, the most commonly reported adverse reactions were: peripheral oedema, headache, flushing, tachycardia and palpitations.

Immune system disorders.

Rare: hypersensitivity.

Nervous system disorders.

Common: headache.

Uncommon: dizziness.

Rare: somnolence, syncope.

Cardiac disorders.

Common: tachycardia, palpitations.

Rare: angina pectoris.

Vascular disorders.

Common: flushing.

Uncommon: hypotension.

Gastrointestinal disorders.

Uncommon: nausea, dyspepsia, upper abdominal pain.

Rare: vomiting, diarrhoea.

Not known: gingival hyperplasia^1, cloudy peritoneal dialysate^1.

Hepatic disorders.

Not known: increased serum transaminase levels^1.

Skin and subcutaneous tissue disorders.

Uncommon: rash, pruritus.

Rare: urticaria.

Not known: angioedema^1.

Musculoskeletal and connective tissue disorders.

Uncommon: myalgia.

Renal and urinary disorders.

Uncommon: polyuria.

Rare: pollakiuria.

General disorders.

Common: peripheral oedema.

Uncommon: asthenia, fatigue.

Rare: chest pain.

^1 Adverse reactions reported from spontaneous reporting during the post-marketing period.

Some dihydropyridine derivatives may rarely cause precordial pain or angina. Very rarely, in patients with existing angina attacks, an increase in frequency, duration and severity may occur. In isolated cases, myocardial infarction may develop.

Lercanidipine does not have a negative effect on blood glucose or serum lipid levels.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua or through the company website https://www.berlin-chemie.ua.

Shelf life.

2 years. Do not use after the expiry date stated on the packaging.

Storage conditions.

Store at temperatures not exceeding 25 °C. To protect from light and moisture, keep the medicine in the original packaging. Store out of reach and sight of children.

Packaging.

14 film-coated tablets in a blister; 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Recordati Industria Chimica e Farmaceutica S.p.A., Italy.

Manufacturer's address.

Via Matteo Civitali, 1 – 20148 Milan (MI), Italy.

Marketing Authorisation Holder.

Menarini International Operations Luxembourg S.A., Luxembourg.

Address of the Marketing Authorisation Holder.

1, Avenue de la Gare, L-1611 Luxembourg, Luxembourg.

Under licence from RECORDATI.